Alzheimer disease (AD) produces a progressive degeneration of the brain that slowly destroys a victim's cognitive abilities. This disease inflicts tremendous social and economic burden on families and society in general. It is projected that more than 200,000 Veterans will be diagnosed with dementia in 2017, with AD the most common cause. Therapeutic options for AD remain very limited and no treatments have been shown to slow the relentless progression of the disease. Pathologically AD is characterized by the presence of extracellular amyloid plaques composed of amyloid-? (A?) derived from amyloid precursor protein (APP) and the abnormal phosphorylation of the microtubule associated protein tau that results in the formation of tangles inside neurons. These protein deposits are associated with a dramatic loss of neurons in the cortex and hippocampus. The mechanistic relationship between these protein accumulations and neurodegeneration is, however, unknown. Synaptic dysfunction and loss of axon terminals are among the earliest recognized changes in AD, suggesting that impairment of mechanisms that maintain integrity of synapses may underlie or contribute to pathology. Removal and replacement of damaged proteins (proteostasis) is a primary mechanism by which cells maintain functional structures such as mitochondria. Clearance is mediated by two interconnected systems-the ubitquitin-proteasome system and the autophagy-lysosome system. Interestingly, recent studies indicate that there may be locally regulated proteostasis programs at presynaptic terminals. In our preliminary data we demonstrate that the autophagy-lysosome system is upregulated specifically at synapses in response to A?. In this Pilot Project we propose to test the hypothesis that presynaptic autophagy plays a crucial role in the neurodegeneration that occurs in AD. To test the hypothesis, we have generated two presynaptically targeted molecular regulators of autophagy - one enhancer and one suppressor. We propose to determine the consequences of altering presynaptic autophagy on an in vitro model of AD as well as a murine model of the disease. At the end of the proposed studies we expect to have a better understanding of autophagy of presynaptic structures and how this process relates to neurodegeneration in AD. This knowledge will hopefully help us to identify novel targets for the treatments that slow the progress of this devastating disease.